This invention relates to prostaglandin-containing lyophilized powders and use thereof to produce aqueous solutions or solid pharmaceutical preparations for enteral, parenteral, and topical application and to processes of preparing prostaglandin-containing lyophilized powders.
Prostaglandins are hydroxy-fatty acids derived from prostanoic acid: ##STR1##
Prostaglandins include both naturally-occurring prostaglandins and synthetic analogs of natural prostaglandins.
Natural prostaglandins include, for example, prostaglandins A.sub.1, A.sub.2, E.sub.1, E.sub.2, E.sub.3, F.sub.1.alpha., F.sub.2.alpha., B.sub.1, B.sub.2, D.sub.1, and D.sub.2. PGE.sub.2 has a cis-5,6-double bond, a trans-13,14-double bond, a C-9-keto group, and an .alpha.-hydroxy group at the 11- and 15-positions of prostanoic acid.
Exemplary of synthetic analogs of natural prostaglandins are C.sub.1 -carboxylic acid esters and amides, 19-oxa-, 17-substituted-.omega.-tris-nor-, and 16-substituted-.omega.-tetra-nor- prostaglandins. Hydroxy groups in the 9-, 11- and/or 15-position can be etherified or esterified, or a 15-hydroxy group can be oxidized to the keto group and be ketalized. Double bonds in the 10,11- or 13,14-position can collectively be substituted by a methylene or hydrogenated.
Prostaglandins are of great interest owing to their remarkable biological and pharmacological characteristics. However, prostaglandins, especially prostaglandin E derivatives, are relatively unstable. Attempts to stabilize prostaglandins using a suitable carrier material have generally been unsuccessful.
Methanolic solutions of prostaglandins PGE.sub.1 and PGE.sub.2 are stable depending on pH, for up to 40 days at room temperature, Eur. J. Pharmacol. 4 (1968) 416-420. However, methanolic solutions are toxic and cannot be employed in medicine.
Solutions of PGE.sub.2 in absolute ethanol can be preserved for at least 6 months at -20.degree. C., Amer. J. Hosp. 30 (1973) 236-239. Ethanolic solutions are unsuitable for medical use without dilution by water or other carrier materials prior to use. Moreover, PGE.sub.2 in ethanol at 4.degree. C. loses 5-12% of its activity within a month and PGE.sub.2 decomposes so rapidly in NaCl solution that only 58-62% of the original activity remains after 15 days. Lipids 8, 10 (1973) 592-594.
In U.S. Pat. No. 3,826,823 are described prostaglandin preparations stabilized with polyvinylpyrrolidone. In a preferred embodiment, a prostaglandin material and polyvinylpyrrolidone are dissolved in methylene dichloride and concentrated by evaporation under vacuum at 50.degree. C. The dry powder obtained from the film, or pharmaceutical preparations made therefrom, can be preserved for 8 months at room temperature. Since 10-1000 parts of polyvinylpyrrolidone are used per 1 part of prostaglandin, the prostaglandin material to be formulated is already present at a very high dilution. Therefore, it is impossible to obtain highly concentrated prostaglandin preparations by this process.
Pharriss, in U.S. Pat. No. 3,882,241, discloses a variety of stabilizing and/or suspending agents for prostaglandins, including polyvinylpyrrolidone.
Monkhouse, U.S. Pat. No. 3,851,052, describes polyvinylpyrrolidone as a binding agent with prostaglandins stabilized by an alkali metal sulfite salt.
Andersen et al., in U.S. Pat. No. 3,723,423, and Zaffaroni, in U.S. Pat. No. 3,845,111, suggest that sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmityl or dioctyl sodium sulfosuccinate are emulsifiers, preservatives and/or wetting agents for formulations of prostaglandin ethers.
Bergstrom, U.S. Pat. No. 3,598,858, notes the use of gelatin, lactose, starches, magnesium stearates, plus auxiliary substances, including preservatives, in prostaglandin formulations.
Therefore, there is a continuing need for prostaglandin-containing lyophilized powders which are stable over a long period of time and suitable for the preparation of aqueous solutions and solid galenic preparations.
This problem is solved by freeze-drying prostaglandin material contained in an aqueous solution containing tris (hydroxymethyl) aminomethane hydrochloride and optionally an inert filler. Thus, addition of tris (hydroxymethyl) aminomethane hydrochloride to prostaglandin material effects a substantial improvement in the stability thereof.
Surprisingly, addition of tris (hydroxymethyl) aminomethane hydrochloride considerably improves stability of prostaglandin E.sub.2 to lyophilization and subsequent storage.